PROJECT SUMMARY This application aims to address the central question of whether brain bioenergetic dysfunction serves as an etiologic mechanism underlying the initiation of late-onset sporadic Alzheimer's disease (sAD). Our overarching hypotheses are that age, sex, and apolipoprotein E (APOE) genetic status?the most potent triad of sAD risk factors?synergistically alter brain energy metabolism, and that bioenergetic changes trigger alterations in amyloid homeostasis and synaptic transmission resulting in the onset of preclinical sAD. The proposed studies will be carried out in three specific aims. Aims 1 and 2 will be performed in novel mouse models that possess genetic conditions analogous to sAD (co-expression of human wild-type APP and human APOE alleles: ?2, ?3, or ?4), while Aim 3 will be conducted in blood samples collected from the aforementioned sAD mouse models and a cohort of healthy, MCI, and early-stage sAD human subjects. Specifically, Aim 1 will examine the combinatory role of age, sex, and APOE status on brain energy and amyloid metabolism to directly assess the hypothesis that age-sex-APOE-mediated bioenergetic changes precede alterations in amyloid homeostasis in the early aging brain. Aim 2 will address the hypothesis that synaptic vesicles function and neurotransmission are significantly affected by alternations in brain bioenergetics. Aim 3 will assess the hypothesis that alterations in brain bioenergetic and cognitive function can be predicted by bioenergetic transcriptional changes in the blood. Our ultimate goals for this research are two-fold: (1) to define the bioenergetic roles and specific processes involved in the development of sAD-risk phenotypes and (2) to identify blood-based bioenergetic transcriptomic biomarkers that are predictive of brain changes in the development of MCI and sAD. Achievement of these goals will advance our understanding of the complex etiology of sAD. More importantly, the findings yielded from these investigations will provide valuable insight into the identification of novel peripheral biomarkers that could potentially be used for early diagnosis of MCI and sAD as well as mechanistic rationales that could guide the development of novel therapeutic strategies that may be utilized for sAD prevention, risk reduction, and early intervention, particularly in the high-risk population of women and APOE4 carriers.